A one-pot, three-component reaction for the synthesis of novel 7-arylbenzo[c]acridine-5,6-diones

Article abstract of DOI:10.1039/c4cc03079f

A one pot domino protocol for an efficient synthesis of 7-arylbenzo[c]acridine-5,6-diones, with a novel nucleus, has been developed by reacting 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and aromatic amines using environmentally benevolent p-tolue

Full text of DOI:10.1039/c4cc03079f

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A one-pot, three-component reaction for the
synthesis of novel 7-arylbenzo[c]acridine-5,6-diones†
Shivani Mahajan,a Sadhika Khullar,b Sanjay K. Mandalb and Inder Pal Singh*a
Cite this: Chem. Commun., 2014,
50, 10078
Received 25th April 2014,
Accepted 10th July 2014
DOI: 10.1039/c4cc03079f
www.rsc.org/chemcomm
A one pot domino protocol for an efficient synthesis of 7-aryl-
benzo[c]acridine-5,6-diones, with a novel nucleus, has been developed
by reacting 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and
aromatic amines using environmentally benevolent p-toluene sulphonic
acid as a catalyst. An exciting feature of this communication is the
reaction mechanism that depends on the reaction solvent.
Naphthoquinone based natural products are known to possess
a myriad of biological activities including antibiotic, antiviral,
antiproliferative, antibacterial, antifungal, insecticidal, anti-
inflammatory, and antipyretic.1 This pharmacophore is known
to impart anticancer activity to a number of drugs like streptonigrin,
mitomycins etc.2 Lapachol and its derivatives have shown a wide
spectrum of therapeutic activities.3 b-Lapachone, a naturally occur-
ring o-naphthoquinone derived from the lapacho tree (Tabebuia
avellanedae), is known to possess anti-trypanocidal, antibacterial,
anti-fungal, and cytotoxic activities.4 Quinoline has functioned as a
‘‘privileged’’ scaffold of several FDA approved drugs.5 The alkaloids
derived from 2-alkylquinoline, chimanine B and chimanine D,
isolated from the leaves of Galipea longiflora, show activity at an
IC90 of 25 mg mLÀ1 against promastigotes of Leishmania braziliensis.6
Skimmianine was found to be active against L. amazonensis.7
Multi-component and domino reactions being efficient and
effective methods in the sustainable and diversity-oriented
synthesis of heterocycles provide one of the most powerful
platforms to access diversity as well as complexity in a limited
number of reaction steps. The development of cheap, novel and
green synthetic route for the synthesis of privileged heterocyclic
Fig. 1 Design of 7-arylbenzo[c]acridine-5,6-dione derivatives based on
anti-leishmanial activity of b-lapachone, skimmianine and chimanine B.
scaffolds of medicinal relevance, a continuing challenge at the
forefront of modern chemistry, can be achieved using multi-
component protocols. Herein, we report our studies to develop
a novel domino protocol for the synthesis of a previously unexplored
7-arylbenzoacridine-5,6-dione nucleus incorporating o-naphthoqui-
none and quinoline moieties (Fig. 1) into a single nucleus
through a multicomponent strategy.
Focusing our interest on anti-leishmanial activity of lapachol
derivatives, the synthesis of the hydroxynaphthalene-1,4-dione
nucleus (4) was attempted by one pot reaction of 2-hydroxynaph-
thalene-1,4-dione (1), benzaldehyde (2) and aniline (3) (see
Scheme 1) and the corresponding product was obtained in
reported yield.8 To our delight, the reaction was observed to
yield altogether different products while changing the sequence
and time of addition.9 Addition of benzaldehyde (2) to a
solution of 2-hydroxynaphthalene-1,4-dione (1) and aniline (3) in
20 mol% of p-TSA that was under reflux in water for 30 minutes,
followed by continuous refluxing for 12 h led to unexpected
reaction products. The resulting reaction mixture was purified
a Department of Natural Products, National Institute of Pharmaceutical Education
and Research, Sector 67, SAS Nagar, Punjab 160062, India.
E-mail: ipsingh@niper.ac.in, ipsingh67@yahoo.com; Fax: +91-172-2214692;
Tel: +91-172-2292144, +91-9815026410
b Department of Chemical Sciences, Indian Institute of Science Education and
Research, Knowledge City, Sector 81, SAS Nagar, Punjab 140306, India
† Electronic supplementary information (ESI) available: Additional information
on this study, detailed experimental procedure and analytical data for all the new
compounds. CCDC 998127. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc03079f
Scheme 1 Synthesis of 2-hydroxynaphthalene-1,4-dione (4).
10078 | Chem. Commun., 2014, 50, 10078--10081
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Table 1 Reaction optimization conditions
S. no. Solvent Catalysta Timeb (min) Timec (h) Temp.d Yielde
1
2
3
4
5
6
7
8
Water
CHCl3
EtOAc
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Water
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
BF3ÁEt2O
ZnCl2
ZnCl2
SnCl2
TiCl4
30
30
30
15
10
0
0
0
0
0
0
0
0
0
12
12
12
12
12
12
6
6
6
6
6
100
60
70
60
60
60
60
60
100
60
60
60
60
60
60
10
16
12
57
64
75
92
25
41
35
12
22
50
78
46
Scheme 2 Optimization of 7-phenylbenzo[c]acridine-5,6-diones.
using column chromatography to give a single spot on TLC.
However, 1H and 13C NMR data indicated that to be a mixture of at
least two compounds. The mixture was subjected to analytical HPLC
that clearly indicated two peaks which were analyzed using LCMS
9
11
12
13
6
6
6
6
(Fig. S1a and b, ESI†) and purified using preparative HPLC to obtain 14
FeCl3
NbCl5
CsCl
5 and 610 in 10% and 49% yields, respectively (Scheme 2), and
15
16
characterized on the basis of spectral data. The HRMS, 1D and 2D
a
0
b
20 mol%. Time at which 2 was added to the reaction mixture of 1
NMR data (Table S1, ESI†) of 5 suggested two possible structures as
c
d
e
and 3 in p-TSA. Reaction time. Reaction temperature (1C). Yield
(%age of product 5) determined using HPLC.
shown in Fig. S2, ESI.† Finally, the structure was confirmed as 5
on the basis of single crystal X-ray crystallography data (Table S2
and Fig. S3–S5, ESI†).11–14 An ORTEP diagram of 5 is shown in
Fig. 2 (for its labelled version, see Fig. S3, ESI†). It forms a 1D linear
supramolecular assembly via C–HÁÁÁO interactions (C15ÁÁÁO1
3.136 Å, symmetry: 1 + x, y, z) and strong p–p interactions (the
centroid–centroid distance: 3.612 Å and 3.627 Å) as shown in
Fig. S4–S5, respectively, in the ESI.† These interactions provide an
extra stability for 5. In order to confirm whether the single crystal
structure represents the bulk material of 5 that will exclusively show
its purity and homogeneity, the experimental and simulated powder
X-ray diffraction patterns were matched (Fig. S6, ESI†).
In search of effective reaction conditions, 2-hydroxynaphthalene-
1,4-dione (1), benzaldehyde (2) and aniline (3) were used in the
model reaction (Scheme 2) to investigate all the variable parameters
like solvent, time, catalyst, the sequence of addition of reagents
and time of addition of reagents and the results are summarized
in Table 1.
During initial attempts, various polar protic, polar aprotic
and non-polar solvents were investigated in the presence of a
catalytic amount of p-toluene sulphonic acid. It was observed that
a variation in solvents resulted in a complete change in reaction
products. Investigational results of polar protic solvent (water)
indicated that the reaction was found to yield 10% of the required
product 5 (entry 1, Table 1). Using water in combination with
other reagents like polyphosphoric acid, PEG 6000 and acetic acid
did not yield the desired product. Polar aprotic solvent (ethyl
acetate) gave 12% of the desired product (entry 3, Table 1). Based
on the solvent screening (see Tables S3–S5, ESI†), the maximum
yield (16%) was obtained using chloroform.15
To the best of our knowledge, condensation of 2-hydroxy-
naphthelene-1,4-dione, aromatic aldehyde and aniline to generate
the acridine nucleus has not been investigated yet. The combi-
nation of a novel skeleton of 5 (containing o-naphthoquinone and
quinoline moieties) and biological activity of compounds like
b-lapachone, chimanine B and skimmianine prompted us to
investigate concise routes to the 7-arylbenzo[c]acridine-5,6-
dione nucleus (Fig. 1).
Considering chloroform as the solvent of choice, we studied
the effect of the addition sequence of reagents with respect to
time. It was observed that the reaction did not yield the desired
product, when 2 was added after 3 h, 2 h and 1 h to the reaction
mixture containing 1 and 3 in p-TSA under refluxing conditions
in chloroform. A continuous decrease in the time of addition of
2 to the reaction mixture leads to a significant rise in the yield
of the required product as summarized in Table S6, ESI.† Here,
the best results were obtained when all the three reactants 1, 2
and 3 were mixed together (entry 7, Table 1).
To study the progress of reaction with time, the reaction was
monitored by HPLC every 30 minutes and the results are
summarized in Table S7 of ESI.16† The optimal reaction time
was found to be 6 h. The yield of 5 decreased after 6 h due to the
formation of non-polar side products as observed in HPLC. The
HPLC analyses revealed the appearance of a peak having a reten-
tion time (tR) of 23 min which could be ascribed to intermediate VI
on the basis of HRMS data (HRMS-ESI m/z calcd for C23H15NO2
[M + Na]+: 360.1000, found: 360.1001 (Fig. S7, ESI†)) during initial
Fig. 2 An ORTEP drawing of 5. Thermal ellipsoids are shown at the 50%
probability level.
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hours, which diminished with time and the peak of the desired
product (5) having tR of 32 min increased to 90% at 6 h (for
chromatograms see Fig. S8 and S9, ESI†).
Thereafter, we screened a range of Lewis acids in order to
obtain better yields (Table S8 of ESI†). The Lewis acid screening
suggested NbCl5 as a surrogate catalyst (entry 15, Table 1) with
78% yield of the required product. Screening with various acidic
catalysts (see Table S9, ESI†) showed that p-TSA was the most
preponderant one. Continuous loading of catalyst did not result in
a significant change in the yield of the reaction indicating 20 mol%
as optimal to obtain the maximum yield of the product. On the
basis of the above studies, the most favourable reaction conditions
for the formation of 5 are as shown in entry 7 in Table 1.
Scheme 4 Proposed mechanism for the formation of 5.
Formation of VI as the principal product under a nitrogen
An exciting feature of this work is the postulated mechanism that atmosphere confirmed that the air-oxidation proceeded in the
depends on the reaction solvent. The variation in solvent i.e. water to reaction. Based on these results, a reasonable mechanism accounting
CHCl3 led to a change in the reaction mechanism, leading to a novel for the observed transformation was proposed (Scheme 4). As outlined
skeleton. Mixing 1, 2 and 3 in the presence of 20 mol% p-TSA in in Scheme 4, the initial condensation of 1 with benzaldehyde (2) gave
water under refluxing for 6 h resulted in 4 (Scheme 1) through the corresponding intermediate VII which subsequently underwent
formation of Schiff base (Scheme S1, ESI†),8 whereas use of CHCl3 nucleophilic addition of aniline to generate intermediate X. Finally,
as solvent gave 5 through the nucleophilic addition of benzaldehyde intermediate X was cyclized followed by aerial oxidation to
at the double bond of 2-hydroxynaphthalene-1,4-dione (1), followed afford product 5.
by reaction with aniline as shown in Scheme 4.
The reaction may seem to resemble Doebner–Miller quinoline
It seems to be reasonable to think that product 5 is the result synthesis (reaction of an a,b-unsaturated carbonyl and aniline) with
of the four distinct events, namely nucleophilic attack of aniline to respect to the substrates 2-hydroxynaphthalene-1,2-dione 1 and
give intermediate III, followed by its acylation at the a-position and aniline 3, however, as per the suggested mechanism, the substrate
cyclization to VI, followed by aerial oxidation to give 5 (Scheme 3). bearing the a,b-unsaturated carbonyl scaffold acts as a nucleophile
To support the above sequence of events, benzoyl chloride was rather than an electrophile as in the conjugate addition step of
added to the mixture of 1 and 3 in p-TSA after 3 h, in both water and Doebner–Miller reaction (discussed in Scheme S2 and Table S10,
chloroform under refluxing conditions, considering in situ benzoyla- ESI†). The enol form of 2-hydroxynaphthalene-1,4-dione acts as
tion of intermediate III, the results showed no product formation a nucleophile to attack carbonyl functionality of benzaldehyde
leading to dereliction of the mechanism discussed in Scheme 3.
to yield an aldol-type intermediate that reacts with aniline. Both
Further, to gain information on the exact mechanistic aspect the steps involving a,b-unsaturated carbonyl are different from those
of the reaction some more reactions were examined: (i) activated proposed for Doebner–Miller reaction (Scheme 4). A Doebner–Miller
benzaldehyde17 was added dropwise to 3, followed by 3 h refluxing type generation of quinoline would have resulted in a different
for Schiff base formation and was added dropwise to 1 and refluxed product (XV) as shown in Scheme S3 (ESI†).
for 6 h; (ii) activated benzaldehyde17 was added dropwise to 1
With the optimized conditions in hand, to delineate this
for nucleophilic addition of benzaldehyde at the double bond of approach, the scope and generality of this protocol were next
2-hydroxynaphthalene-1,4-dione (1), followed by 3 h refluxing, accessed by employing various aromatic aldehydes (7a–n) and
which was added dropwise to 3 and refluxed for 6 h; (iii) activated anilines (3a–g) to synthesize the corresponding 7-arylbenzo-
117 was added dropwise to 3, followed by 3 h refluxing and was acridine-6,11-diones. An assembly of nineteen compounds was
added dropwise to 2 and refluxed for 6 h. The favourable outcome synthesized using this protocol (Table 2) and the purity of
of experiment (ii) led to the conclusion that the reaction proceeded all the synthesized compounds was confirmed using qNMR
through the nucleophilic addition of benzaldehyde at the double (Table S11, ESI†).18 The reaction could tolerate various sub-
bond of 2-hydroxynaphthalene-1,4-dione (1), as shown in Scheme 4. stitutions on aromatic aldehydes. Notably, aromatic aldehydes
bearing electron withdrawing substituents e.g. 4-Cl, 4-Br, 4-F,
4-NO2, 4-CF3 etc. at the aryl ring afforded the desired products
with excellent efficiency. It was pleasing to find that sterically
bulky 2-naphthaldehyde also reacted very efficiently. The failure of
reaction with aromatic aldehydes bearing o/p electron releasing
groups (OCH3, OH), substituted amine, morpholine, pyrrolidine,
piperidine can be attributed to the mechanism of the reaction.
The result is not surprising in the light of the reduced electro-
philicity of the aldehyde due to the effect of electron releasing
groups. To further evaluate the substrate scope, differently
substituted anilines were investigated. The reaction worked well
Scheme 3 Surmised mechanism for the formation of 5.
10080 | Chem. Commun., 2014, 50, 10078--10081
with anilines bearing electron releasing groups (3-Me, 3-OMe
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Table
diones
2
Diversity of uniquely decorated 7-arylbenzo[c]acridine-5,6-
Anti-Cancer Agents Med. Chem., 2006, 6, 489–499; (e) H. Chang,
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R. T. Hanlin, S. Hernandez-Ortega, A. Saucedo-Garcıa, J. M. Muria-
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Gonzalez and A. L. Anaya, Phytochemistry, 2008, 69, 1185–1196;
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(g) E. Braud, M. Goddard, S. Kolb, M. Brun, O. Mondesert,
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Physiol., 2007, 211, 522–532; (d) D.-O. Moon, Y. H. Choi, N.-D. Kim,
Y.-M. Park and G.-Y. Kim, Int. Immunopharmacol., 2007, 7, 506–514;
(e) A. L. Bodley and T. A. Shapiro, Proc. Natl. Acad. Sci. U. S. A., 1995,
92, 3726–3730.
Entry
R1
R2
Yielda
1
2
3
4
5
6
7
8
4-Ph-Cl
4-Ph-Cl
4-Ph-Br
4-Ph-Br
4-Ph-CN
4-Ph-CN
4-Ph-CF3
4-Ph-CF3
2-Napthyl
2-Napthyl
4-Ph-F
4-Ph-F
4-Ph-NO2
4-Ph-NO2
Ph
OCH3
CH3
OCH3
CH3
OCH3
CH3
OCH3
CH3
OCH3
CH3
OCH3
CH3
OCH3
CH3
3,4-Methylenedioxy
1-Naphthyl
3-F
91
87
82
80
91
88
79
81
84
73
76
72
87
86
90
83
85
82
9
10
11
12
13
14
15
16
17
18
5 M. Negosanti, V. Bettoli, R. Valenti, P. Patrone and G. Celasco,
G. Ital. Dermatol. Venereol., 1985, 120, 17–23.
´
6 (a) A. Fournet, R. Hocquemiller, F. Roblot, A. Cave, P. Richomme
Ph
Ph
Ph
and J. Bruneton, J. Nat. Prod., 1993, 56, 1547; (b) A. Fournet,
˜
´
A. Angelo, V. Munoz, R. Hocquemiller, A. Cave and J. Bruneton,
Antimicrob. Agents Chemother., 1993, 37, 859; (c) A. Fournet,
J. C. Gantier, A. Gautheret, L. Leysalles, M. H. Munos, J. Ayrargue,
3-Cl
a
Isolated yield.
´
H. Moskowitz, A. Cave and R. Hocquemiller, J. Antimicrob.
Chemother., 1994, 33, 537.
˜
´
7 A. Fournet, A. A. Barrios, V. Munoz, R. Hocquemiller and A. Cave
Bruneton, Antimicrob. Agents Chemother., 1993, 37, 859–863.
8 M. Dabiri, Z. N. Tisseh and A. Bazgir, Dyes Pigm., 2011, 89, 63–69.
9 Benzaldehyde was added after 30 minutes to the refluxing mixture
of aniline and 2-hydroxynaphthalene-1,4-dione in 20 mol% of p-TSA
and the resulting mixture was refluxed for 12 h. The reported
procedure is the concomitant mixing of all the reagents and reflux-
ing for 6 h.
and 3,4-methylenedioxy) as well as with sterically bulky
1-naphthylamine but not with electron withdrawing groups
(F, CF3, CN, Cl, Br and NO2) at the o- and the p-position.
It was pleasing to observe that the reaction could tolerate
electron withdrawing groups at the m-position. The results
are convincing for anilines bearing electron withdrawing
groups at the o- and the p-position due to the effect of reduced
nucleophilicity of the substrate.
In summary, we have developed a novel one pot domino
protocol for the efficient synthesis of 7-arylbenzo[c]acridine-5,6-
diones, a class of previously unreported compounds whose activity
deserves more investigation, in 70–90% yields along with the
mechanistic details. The simple experimental procedure, utilization
of an inexpensive, readily available and environmentally friendly
catalyst and excellent yields are the advantages of the present
methodology. The reaction enriches the toolbox for the synthesis
of o-naphthoquinone heterocycles which could be applied in
medicinal chemistry. Further efforts on the exploration of their
biological activities are in progress.
10 C. S. Lisboa, V. G. Santos, B. G. Vaz, N. C. Lucas, M. N. Eberlin and
S. J. Garden, J. Org. Chem., 2011, 76, 5264–5273.
11 Crystal data for 5: C23H13NO2, M = 335.34, monoclinic, space group
P21/m, a = 9.638(6) Å, b = 7.105(5) Å, c = 11.862(8) Å, a = 901,
b = 95.858(11)1, g = 901, V = 808.0(9) Å3, Z = 2, Dc = 1.378 mg cmÀ3
,
m (Mo-Ka) = 0.088 mmÀ1, T = 296 K, 6011 reflections collected.
Refinement of 721 reflections (148 parameters) with I 4 2s(I)
converged at a final R1 = 0.0610, wR2 = 0.1451, GOF = 0.959.
CCDC 998127.
12 APEX2, SADABS and SAINT; Bruker AXS inc: Madison, WI, USA, 2008.
13 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
64, 112–122.
14 C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edginton, P. McCabe,
E. Pidocck, L. Rodriguez-Monge, T. Taylor, J. Van de Streek and
P. A. Wood, J. Appl. Crystallogr., 2008, 41, 466–470.
15 p-Toluene sulphonic acid was added to 2-hydroxynaphthalene-1,4-
dione (1), followed by the addition of aniline (2). The mixture was
dissolved in respective solvents (discussed in Tables S1–S3, ESI†)
and allowed to reflux for 30 minutes, followed by the addition of
benzaldehyde (3) and refluxing for further 12 h. The reactions were
analysed by HPLC.
16 The mobile phase composition used for the HPLC gradient program
for the analyses was acetonitrile : water gradient from 10 : 90 at
0 min to 100 : 0 at 40 min.
The authors are thankful to the Director, NIPER, for the
support for this work. Shivani Mahajan also thanks CSIR,
New Delhi, for the award of the senior research fellowship. The
use of X-ray facility at IISER, Mohali, is greatly acknowledged.
17 These experiments were performed considering both acid activation
(20 mol% p-TSA) and metal activation (20 mol% NbCl5) of the
respective reagent for 10 minutes, to confirm the mechanism as
per the two possibilities considered (see Fig. S2, ESI†). All the three
cases were explored in both water and chloroform.
Notes and references
1 (a) Y. Kumagai, Y. Shinkai, T. Miura and A. K. Cho, Pharmacol.
Toxicol., 2012, 52, 221–247; (b) A. V. Pinto and S. L. de Castro,
Molecules, 2009, 14, 4570–4590; (c) P. Babula, V. Adam, L. Havel and
R. Kizek, Curr. Pharm. Anal., 2009, 5, 47–68; (d) R. P. Verma, 18 S. Mahajan and I. P. Singh, Magn. Reson. Chem., 2013, 51, 76–81.
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Chem. Commun., 2014, 50, 10078--10081 | 10081